Octahydro-6, 10-dioxo-6h-pyridazino/1,2-a/ /1,2/diazepin-1-carboxylic acid, derivatives, preparation method and use for preparing therapeutically active compounds

ABSTRACT

The invention concerns compounds of formula (I) in SR configuration or in the form of a SR+SS mixture, wherein R represents a hydrogen atom, an alkyl or aralkyl radical containing up to 18 carbon atoms, the amine function being free or protected. The compounds can be used for preparing active principles for medicines.

This application is a 371 of PCT/FR99/00981 filed on Apr. 26, 1999.

The present invention relates to new derivatives ofoctahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylicacid, their preparation process and their use in the preparation oftherapeutically active compounds. U.S. Pat. No. 4512924, WO 93 23403,U.S. Pat. No. 5723602, WO 97 22619, U.S. Pat. No. 5,656,627 and WO 33751describe derivatives of9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylicacid, the amine of which is optionally protected in the form of aphthalimido of 1S,9S configuration, as a starting product for thepreparation of products as medicaments. Obtaining the SS diastereoisomeris carried out by separation methods, in particular by crystallizationor chromatography, in a stage upstream of the cylization.

A subject of the invention is the compounds of formula

of SR configuration or in the form of an SR+SS mixture, in which Rrepresents a hydrogen atom, an alkyl or aralkyl radical containing up to18 carbon atoms, the amine function being able to be free or protected.

R represents for example an H, methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl or tertbutyl radical, or a benzyl or naphthyl radical.When the amine function is protected, the protection can be carried outaccording to standard methods for the protection of amines.

A particular subject of the invention is the compounds corresponding toformula (IA):

of SR configuration or in the form of an SR+SS mixture, in which Rretains its previous meaning and either R₁ represents

radical

Ra, Rb, Rc and Rd representing an alkyl or aryl radical containing up to18 carbon atoms, or a mono or polycyclic radical containing one or moreheteroatoms, X representing a hydrogen atom, an alkyl radical containingup to 8 carbon atoms or an aryl radical containing up to 14 carbonatoms, and R₂ represents a hydrogen atom,

or R₁ and R₂ form together a mono or polycyclic radical containing oneor more heteroatoms.

For example, in order to protect the amines, cyclic compounds can beused, for example the

radicals, or also the

radical.

A more particular subject of the invention is the compounds of formula(IA) in which R₁ and R₂ together form a polycyclic radical containingone or more heteroatoms and in particular the compounds corresponding toformula (1A₁):

of SR configuration or in the form of an SR+SS mixture.

A particular subject of the invention is the compounds of formula (I) inwhich R represents a methyl radical, of SR configuration or in the formof an SR+SS mixture.

A subject of the invention is also a process characterized in that acompound of formula (II):

in which alk represents an alkyl radical containing up to 8 carbon atomsand Hal represents a halogen atom, is subjected to the action of acompound of formula (III):

in which Aryl represents an aryl radical containing up to 14 carbonatoms, in order to obtain the compound of formula (IV):

which is subjected to the action of a basic agent, in order to obtainthe compound of formula (V):

which is optionally subjected to the action of an alkylation agent inorder to obtain the compound of formula (VI):

which is subjected to the action of a compound of formula VII):

in which Hall represents a halogen atom and Ar represents an aryl oraralkyl radical containing up to 18 carbon atoms, R₁ and R₂ retainingthe same definition as previously, in order to obtain the compound offormula (VIII):

of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a hydrogenation agent in order to obtain thecompound of formula (IX):

of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a condensation agent in order to obtain thecorresponding compound of formula (IA), then if desired, the aminefunction is released in order to obtain the compound of formula (I) inwhich the amine function is free.

In a preferred embodiment:

Hal and Hal₁ represent a chlorine atom,

alk represents an alkyl radical containing up to 4 carbon atoms,

Aryl represents a phenyl or naphthyl radical,

aralkyl represents a benzyl radical,

the reaction between the compounds of formula (II) and formula (III)takes place in the presence of a base for example in the presence of analkaline carbonate such as potassium carbonate,

the basic agent which is reacted on the compound of formula (IV) issodium or potassium hydroxide,

the alkylation agent which is reacted on the compound of formula (V) isan alcohol for example methanol,

the condensation between the compounds (VI) and (VII) is carried out inthe presence of a base such as pyridine, TEA, diisopropylamine,

the hydrogenation agent is for example hydrogen in the presence ofpalladium on carbon, palladium dihydroxide in the presence of talc,rhodium in the presence of alumina, ruthenium on carbon, or in thepresence of Raney nickel,

the cyclization is carried out in the presence of SOCl₂ or PCl₅ oractivated esters or in the presence of dehydration agents such as PTSA,

the release of the amine can be carried out using hydrazine.

The products (IV), (VII), (VIII) and (IX) used during the process arenew products and are in themselves a subject of the present invention.

A more particular subject of the invention is the products thepreparation of which is given hereafter in the experimental part and inparticular the racemic mixture.

A subject of the invention is also the use characterized in that acompound of formula (I) in the form of an SS,SR mixture, or in SR form,is subjected to the action of a deracemization agent of the asymmetriccarbon carried by the ring with 6 members, in order to obtain thecompound of formula (Iopt):

in SS form, in which the amine function is free or protected and Rretains its previous meaning.

A more particular subject of the invention is the use of the compoundsof formula (IA) defined above, for the preparation of compounds offormula (IAopt):

in the SS form, in which R, R₁ and R₂ retain their previous meaning.

A more particular subject of the invention is the use characterized inthat R represents a methyl radical, and that in which the amine functionis protected in the form of phthalimido.

A more particular subject of the invention is the use characterized inthat the deracemization agent is a base, more especially a strong base,for example an alkaline or alkaline-earth alcoholate such as sodium orpotassium methylate, sodium or potassium terbutylate, or a lithiatedamine such as LDA.

A quite particular subject of the invention is the use describedhereafter in the experimental part for preparing:

(1s-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2] diazepine-1-carboxylate.

The product of formula (I) of SS configuration in which R is a terbutylradical and the amine is protected in the form of phthalimido, isdescribed for example in the Patent EP 94095, this is an intermediateproduct in the synthesis of products having therapeutic properties.

The products of formula (I) generally can be used for the synthesis ofmedicaments as indicated in the above patent.

The following examples illustrate the invention without limiting it.

EXAMPLE 1(1S-cis)Methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylateand Methyl(1R-Trans)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a)[1,2]diazepine-1-carboxylate.

a) Preparation of 2,5-Dibromopentanoic Acid

39 ml of bromine is added to a mixture of 106 g of 5-bromo pentanoicacid and 1 ml of phosphorus tribromide. The reaction mixture is taken to70˜80° C. for 16 hours 30 minutes. The reaction medium is taken to 100°C. for 15 minutes, then allowed to return to ambient temperature. 147 gof sought product is obtained.

b) Preparation of Ethyl 2,5-Dibromopentanoate

24.37 g of oxalyl chloride is added to a mixture containing 50 g of theproduct prepared in the preceding stage, 15 drops of DMF, and 300 ml ofmethylene chloride. The reaction mixture is maintained under agitation,at ambient temperature, until the reaction is complete. The reactionmixture is cooled down to 10° C. and 50 ml of ethyl alcohol is added.The reaction medium is agitated for 30 minutes at 10° C., left to returnto ambient temperature and agitated for 3 hours at ambient temperature.After bringing to dryness, the sought product is obtained.

c) Preparation of Bis(phenylmethyl)1,2-hydrazinedicarboxylate

1.5 litres of methanol and 2s g of hydrazine monohydrate at 80% areplaced under nitrogen. The reaction medium is cooled down to 0° C. and75 g of benzyl chloroformate is introduced at 0° C., then another 75 gof benzyl chloroformate is introduced at the same time as a solution of93 g of sodium carbonate in 1100 ml of demineralized water. The reactionmixture is maintained at 0° C. for 1 hour, followed by separating andwashing by displacement with a mixture of 100 ml of methanol and 100 mlof water, then washing by displacement with 500 ml of water at 0° C.After drying, 107.6 g of sought product is obtained.

d) Preparation of (S)3-Ethyl-1,2-bis(phenylmethyl)-tetrahydro-1,2,3-pyridazinetricarboxylateand (R)3-Ethyl-1,2-bis(phenylmethyl)-tetrahydro-1,2,3-pyridazinetricarboxylate

A suspension of 12.1 g of the product of ethyl 2,5-dibromopentanoate and50 cm³ of diglyme is introduced at 20˜25° C. into a suspensioncontaining 10.42 g of bis(phenylmethyl) 1,2-hydrazinedicarboxylate, 65ml of diglyme and 8.26 g of potassium carbonate.

The suspension obtained is heated at 90° C. Agitation is maintained for48 hours, followed by cooling down to 20° C., pouring into a solutioncontaining 50 ml of 2N hydrochloric acid and 150 ml of a mixture ofwater and ice, extracting with ethyl acetate, washing with water,drying, filtering, rinsing with ethyl acetate and drying. The productobtained is chromatographed on silica (elution heptane 40, AcOEt 20) and10.71 g of sought product is obtained.

e) Preparation of (S)1-(Phenylmethyl)-tetrahydro-1,3(2H)-pyridazinedicarboxylate and (R)1-(Phenylmethyl)-tetrahydro-1,3(2H)-pyridazinedicarboxylate

A solution containing 23.25 g of the product of the previous stage and80 ml of ethanol is introduced into 338 ml of a solution of sodiumhydroxide in ethanol at 40 g per litre. Agitation is maintained for 5hours 30 minutes and 57 ml of 2N soda is added. The reaction mixture ismaintained under agitation for 30 hours. 141 ml of a solution of 2Nhydrochloric acid is added. 260 ml of the reaction mixture is distilledunder 80˜90 millibars. Extraction is carried out with dichloromethane,20 ml of ethanol is added, followed by washing with a mixture ofwater-normal solution of soda The aqueous phases are extracted withdichloromethane. The aqueous phases are combined, agitated and acidifiedwith 135 ml of a 2N solution of hydrochloric acid. Extraction is carriedout with dichloromethane, followed by washing with water, drying,filtering, washing with methylene chloride, concentrating and drying.146 ml of isopropyl ether is added, followed by agitation for 1 hour at20° C., filtering, washing, concentrating and drying. 11.41 g of soughtproduct is obtained.

f) Preparation of (S) 3-Methyl1-(Phenylmethyl)tetrahydro-1,3(2H)-pyridazinedicarboxylate and (R)3-Methyl 1-(Phenylmethyl)tetrahydro-1,3(2H)-pyridazinedicarboxylate

220 ml of methanol and dehydrated paratoluene sulphonic acid (preparedfrom monohydrated PTSA and 12 ml of dichioromethane) are added to 11.05g of the product prepared in the previous stage. The suspension obtainedis maintained under agitation for 15 hours, heated to 65° C. andmaintained under agitation for 6 hours 30 minutes. After cooling down to5° C., 5.5 ml of a 10% solution of sodium bicarbonate is added, followedby concentrating under reduced pressure, taking up in a mixture of 100ml of dichloromethane and 100 ml of water. Agitation is carried out,followed by decanting, washing the organic phase, extracting withdichloromethane, drying, filtering and concentrating. 11.39 g of soughtproduct is obtained.

g) Preparation of [3S-[2(R*),3R*]]3-Methyl 1-(Phenylmethyl)2-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,5-dioxo-5-(phenylmethoxy)pentyl]tetrahydro-1,3(2H)pyridazineDicarboxylate and [3R-[2(S*),3R*]]3-Methyl 1-(Phenylmethyl)2-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,5-dioxo-5-(phenylmethoxy)pentyl]Tetrahydro-1,3(2H)pyridazine Dicarboxylate

A solution containing 11.01 g of the product prepared in the previousstage and 50 ml of dichloromethane is introduced over 1 hour at about 4°C. into a solution containing 19.88 g of phenylmethyl(S)-gamma-(chlorocarbonyl)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-butanoateand 100 ml of dichloromethane. Agitation is carried out for 30 minutesat 4° C. and 4.15 ml of pyridine in 25 ml of dichloromethane isintroduced over 1 hour 30 minutes. Agitation is maintained for 15 hourswhile slowly allowing the reaction medium to return to ambienttemperature, followed by concentrating under reduced pressure, taking upin 200 ml of ethyl acetate, washing with a saturated solution of sodiumacid carbonate, agitating for 30 minutes, decanting, washing with asaturated solution of sodium acid carbonate, agitating and decanting.The reaction medium is washed with a solution containing 5 ml of anormal solution of hydrochloric acid and 25 ml of water, then with asaturated aqueous solution of sodium chloride and dried. Extraction iscarried out with ethyl acetate, followed by concentrating and drying.25.2 g of sought product is obtained.

h) Preparation of[6S-[(1(R*),6R*[]-1,3-Dihydro-1,3-dioxo-gamma-[[6-(methoxycarbonyl)-tetrahydro-1(2H)-pyridazinyl]carbonyl]-2H-isoindole-2-butanoicAcid and[6R-[(1(S*),6R*]]-1,3-Dihydro-1,3-dioxo-gamma-[[6-(methoxycarbonyl)-tetrahydro-1(2H)-pyridazinyl]carbonyl]-2H-isoindole-2-butanoicAcid

20.23 g of the product of the previous stage, 250 ml of THF and 3.03 gof palladium at 10% on carbon are introduced into a hydrogen apparatus.Hydrogen is passed through for 3 hours, another 3.03 g of catalyst isadded. Hydrogenation is continued for 22 hours, followed by filtering,washing with THF and evaporating. 25 ml of isopropanol is added,followed by concentrating, driving off the THF, 15 ml of isopropanol isadded. A suspension is obtained to which 100 ml of isopropyl ether isadded, followed by agitation under nitrogen for 2 hours, separating,washing with isopropyl ether with 5% isopropanol. After separating anddrying, 9.5 g of sought product is obtained.

I) Preparation of(1S-cis)Methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino{1,2-a][1,2]diazepine-1-carboxylateand(1R-Trans)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino{1,2-a][1,2]diazepine-1-carboxylate

A solution containing 1 ml of thionyl chloride and 40 ml of methylenechloride is added at 5° C. to a mixture containing 4.038 g of theproduct of the previous stage, 40 ml of dichloromethane and 0.4 ml ofdimethylformamide. Agitation is carried out for 3 hours and 30 minutes.The temperature is left to rise towards 20° C., followed by agitationfor one hour 30 minutes and concentrating. A solution containing 0.15 mlof thionyl chloride and 5 ml of methylene chloride is added. Thereaction mixture is maintained under agitation at about 20° C. for 16hours, followed by cooling down to about 5° C. and 27 ml of a saturatedaqueous solution of sodium acid carbonate is introduced. Agitation iscarried out for 30 minutes, followed by decanting and washing with asolution containing 10 ml of sodium bicarbonate and 40 ml ofdemineralized water. Agitation is carried out 3 minutes, followed bydecanting, extracting the aqueous phases with methylene chloride,drying, filtering, washing with methylene chloride and concentratingunder reduced pressure. 3.85 g of sought product is obtained.

Use of(1S-cis)Methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino{1,2-a][1,2]diazepine-1-carboxylate

A solution containing 0.029 g of potassium terbutylate and 0.3 ml of DMFis introduced at a temperature of −45°/−48° C. over 1 hour 30 minutesinto a mixture containing 0.194 g of the product of Example 1, 1.5 ml ofdimethylformamide and 0.75 ml of terbutanol. The mixture is maintainedunder agitation for 1 hour and after cooling down to −50° C., 0.4 g ofpowdered ammonium chloride is introduced. Agitation is carried out for10 minutes at −45° C., 1 ml of ammonium chloride at 20% is addedsuccessively twice whilst agitating again for 10 minutes after eachaddition. 2 ml of demineralized water is added, followed by extractingwith ethyl acetate, washing with demineralized water, decanting,concentrating and drying. 0.166 g of product is obtained. α_(D)=−75.3°(1% in methanol)

What is claimed is:
 1. A process for the preparation of a compound ofthe formula

of SR configuration or a SR+SS mixture wherein R is selected from thegroup consisting of hydrogen, alkyl of up to 18 carbon atoms and aryland aralkyl of up to 18 carbon atoms and the —NH₂ is free or protected,comprising reacting a compound of the formula

where Hal is halogen and alk is a alkyl of 1 to 8 carbon atoms with acompound of the formula

when Aryl is a aryl of up to 14 carbon atoms to form a compound of theformula

reacting the latter with a basic agent to form a compound of the formula

optionally subjecting the compound of Formula IV to an alkylating agentto form a compound of the formula

reacting the latter with a compound of the formula

wherein Hal₁ is halogen, Ar is aryl or aralkyl of up to 18 carbon atoms,R₁ is selected from the group consisting of

R_(a), R_(b), R_(c) and R_(d) are individually selected from the groupconsisting of alkyl of up to 18 carbon atoms, aryl of up to 18 carbonatoms and monocyclic and polycyclic groups containing at least onenitrogen atom, X is selected from the group consisting of hydrogen,alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms and R₂ ishydrogen or R₁ and R₂ together with the nitrogen form a monocyclic orpolycyclic with at least one heteroatom to obtain a compound of theformula

of SR configuration on a SR+SS mixture, reacting the latter with ahydrogenation agent to form a compound of the formula

of SR configuration or a SR+SS mixture, reacting the latter with acondensation agent to obtain a compound of the formula

and optionally deprotecting the amine group to obtain a compound offormula I wherein the amine is free.
 2. A process for the preparation ofa compound of the formula

comprising reacting a compound of the formula

of SR configuration or a SR+SS mixture wherein R is selected from thegroup consisting of hydrogen, alkyl of up to 18 carbon atoms and aryland aralkyl of up to 18 carbon atoms and the —NH₂ is free or protected,with a deracemization agent of the asymmetric carbon carried by the6-member ring to obtain the formula Iopt in SS form with the amine freeor protected.
 3. A process for the preparation of a compound of theformula

comprising reacting a compound of of the formula

of SR configuration or a SR+SS mixture wherein R is selected from thegroup consisting of hydrogen, alkyl of up to 18 carbon atoms and aryland aralkyl of up to 18 carbon atoms and the —NH₂ is free or protected,with a deracemization agent of the asymmetric carbon carried by the6-member ring to obtain the formula Iopt in SS form with the amine freeor protected.
 4. The process of claim 2 wherein R is methyl.
 5. Theprocess of claim 2 wherein the —NH₂ is protected by phthalimido.
 6. Theprocess of claim 2 wherein the deracemization agent is a base.
 7. Theprocess of claim 6 wherein the base is selected from the groupconsisting of an alkali metal alcoholate, an alkaline earth metalalcoholate and a lithiated amine.
 8. The process of claim 3 wherein thefinal product is (is-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a] [1,2]-diazepine-1-methyl-carboxylate.